This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at baseline and at progression. Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall response rate and duration to this combination will also be assessed.

The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry.

Secondary Outcome Measures:

BRAF and MEK inhibition associated with new functional mutations in the approximately 150 oncogenes [ Time Frame: One year ] [ Designated as safety issue: No ]

The secondary outcome measure is to explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll in a correlative study, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, MAP3K8 or COT, and PTEN).

Kinome signature predictive of resistance [ Time Frame: One year post treatment ] [ Designated as safety issue: No ]

Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.

Patients will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival (no tumor measurement per study protocol will be necessary after progression). Response measured radiographically via RECISTv1.1.

Patients who come off therapy for reasons other than progression will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival.Response measured radiographically via RECISTv1.1.

Progression-free survival will be evaluated using the Kaplan-Meier statistical method

Rate of Overall Survival (OS) [ Time Frame: One year post treatment ] [ Designated as safety issue: No ]

Patients will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival.

Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

Drug: BRAF inhibitor dabrafenib and MEK inhibitor trametinib

Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

Other Names:

BRAF Inhibitor Dabrafenib GSK2118436

MEK Inhibitor Trametinib GSK1120212

Detailed Description:

The present phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of BRAF and MEK inhibition. Overall response rate and duration to this combination will also be assessed.

Tissue will be collected at baseline and at progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit. We anticipate that up to 50% of patients may continue on therapy post-progression for 2-8 weeks.

BRF113220, the phase I/II trial of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this combination, and to determine the recommended phase 2 doses (RP2D) for each agent. Expansion cohorts at the RP2D for these drugs in combination were included in the phase I to characterize the safety in more detail, and to explore the efficacy of this combination. The combination was well tolerated as described in section 1.5, with decreased frequency of rash compared to either agent alone and with just 1 report of cutaneous SCC.

This proposed study will utilize the RP2D determined in the Phase I/II study: trametinib 2mg QD and dabrafenib 150 mg BID. Despite a very promising overall response rate of 81%, these patients will also likely go on to develop resistance as a result of new resistance mutations, and given the cooperative signaling network of kinases that sense inhibition of key nodal kinases and induce compensatory responses that offset pharmacological intervention. The study objectives are as follows: Objectives Primary Objective To identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors, and to determine a kinome signature predictive of resistance to BRAF/MEK inhibition in stage III/IV melanoma Secondary Objectives To explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll in LCCC1108, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, MAP3K8 or COT, and PTEN) To determine the overall response rate (ORR: complete response + partial response) as measured via RECISTv1.1 To estimate the duration of ORR as measured via RECISTv1.1 To estimate progression-free survival (PFS) as defined by RECISTv1.1 To estimate the rate of overall survival (OS) at 1 year from day 1 of treatment

Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Subject must meet all of the inclusion criteria to participate in this study:

PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment)

Albumin >2.5 g/dL

Total bilirubin <1.5 x ULN

AST and ALT < 2.5× ULN

CrCl ≥50mL/min per Cockcroft-Gault Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. Effective contraception is defined as any medically recommended method (or combination of methods) as per standard of care, including abstinence. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described from D1 of treatment, throughout the treatment period, and for 16 weeks after the last dose of study treatment.

In women of child-bearing potential, negative serum pregnancy test within 48 hours prior to day 1 of study treatment Measurable disease as defined by RECIST v1.1 Able to swallow and retain oral medication Left ventricular ejection fraction by ECHO ≥ institutional lower limit of normal

Exclusion Criteria:

Any subject meeting any of the following exclusion criteria at baseline will be ineligible for study participation:

Patients with a history of a prior malignancy are excluded unless they have been disease free for 3 or more years or unless they have a completely resected non-melanoma skin cancer, and/or subjects with indolent second malignancies.

Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib (GSK2118436), vemurafenib, and LX281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib (GSK1120212), AZD6244, and RDEA119); NOTE: There is no limit to the number of other prior therapies, and patients may be previously untreated.

Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

Active GI or intracranial hemorrhage

History or evidence of cardiovascular risk including any of the following:

QTc ≥ 480 msec;

History or evidence of current clinically significant uncontrolled arrhythmias;

o Exception: Subjects with controlled atrial fibrillation for >30 days prior to D1 of study treatment are eligible.

Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.

History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency

Brain metastases are excluded unless:

All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), AND

Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for ≥ 12 weeks prior to D1 of study treatment (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND

Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to D1 of study treatment, AND

NOTE: if study subject has history of brain metastasis, but currently has no evidence of disease in brain (NED), confirmation by two consecutive scans separated by ≥6 weeks prior to D1 of treatment is required.

Pulmonary embolism on active therapy History of interstitial lung disease or pneumonitis Known HIV, Hepatitis B or C infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed) Currently active GI disease, or prior surgery that may affect ability to absorb oral medications

History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):

Predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)

Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as:

Evidence of new optic disc cupping

Evidence of new visual field defects

Intraocular pressure > 21 mm Hg Currently receiving cancer therapy (chemotherapy, radiotherapy, immunotherapy, or biologic therapy) NOTE: palliative radiation therapy is permitted for non-target lesions that are either new or present at baseline provided total dose does not exceed 30 Gy Use of other prohibited medications within 5 half-lives or 14 days prior to the first dose of study drugs or requires any of these medications while receiving medication on this study Pregnant or lactating female

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01726738